ABSTRACT ? Project 3 The idea that dietary ?3 polyunsaturated fatty acids (?3 PUFAs), which are high in fish oils and other marine diet constituents, have cardioprotective and other beneficial health properties has captured the attention of the scientific community for more than a generation. Multiple mechanisms could account for the proposed health benefits of ?3 PUFAs. However, with regard to cardioprotection, there is an especially interesting mechanistic link to altered platelet function and a reduced propensity for thromboembolism. In our Alaskan Native (AN) population, many of whom still adhere to a traditional marine-based diet, we have found a strong association between the dietary ?15N biomarker and reduced platelet function. Furthermore, our preliminary data suggest that CYP4F2*3 gene variation, which defines hepatic vitamin K status, also could be a modifier of platelet response. Therefore, we have formulated the central hypothesis that both genetic and dietary factors contribute to inter-individual differences in the basal function of platelets and their response to inhibitors such as aspirin in AI/AN populations of Alaska and the Northwest. Three specific aims have been designed to test this hypothesis. In Aim 1 we will determine if the red blood cell ?15N together with genetic variation in CYP4F2 and the aspirin response gene PEAR1, are associated with inter-individual differences in plasma sP-selectin levels in a cross-section of AI/AN and non-Native populations of Alaska, Washington and Montana. Aim 2 will test whether there is a difference in platelet ?3 PUFA, thromboxane B2 and 20-HETE concentrations between individuals with extreme ?3 PUFA intake phenotypes (i.e. the 0-10 and 90-100 percentiles) and whether these associations are modified by CYP4F2 genotype. Finally, Aim 3 will determine whether, for the same stratified extremes of ?3 PUFA intake phenotype, there is a difference in platelet aggregation under basal and aspirin- treated conditions, and whether those associations are modified by CYP4F2 and PEAR1 gene variation. Collectively, these innovative studies will evaluate unique gene x environment interactions and advance our understanding of the pharmacogenomics of platelet activation and aspirin drug response in the AN community.